Deciphering molecular mechanism behind conformational change of the São Paolo metallo-β-lactamase 1 by using enhanced sampling.

The São Paolo metallo-β-lactamase-1 (SPM-1) plays an important role in drug resistance of β-lactam antibiotics and bindings of zinc ions produce significant effect on the conformations of SPM-1. Thus, it is of significance for understanding function of SPM-1 to probe the conformational changes of SPM-1 induced by bindings of zinc ions. Because replica-exchange molecular dynamics (REMD) simulations can efficiently improve conformational samplings of proteins, REMD and normal mode analysis (NMA) were performed on three systems, including SPM-1 with non-zinc ions, single zinc ion and double zinc ions, to decipher molecular mechanism of conformational changes for SPM-1. The results suggest that binding of double zinc ions induces a closed state of SPM-1, while SPM-1 with binding of non-zinc and single zinc ion mainly exists as an open conformation. The analysis of interaction network between residues was carried out by using the program Ring 2.0. The results show that binding of double zinc ions highly enhances the stability of the π-π interaction network consisting of F60, Y61, F82, F152, Y153 and Y226, two hydrogen bonds between E83 and R161 as well as the salt bridge interaction between E151 and K159 compared to the SPM-1 with non-zinc or single zinc ion, which better stabilizes the closed conformation of SPM-1. Thus, the closed conformation of SPM-1 induced by bindings of double zinc ions is important in catalysis and determining inhibitor selectivity. Meanwhile, this work may provide useful theoretical hints for design of potent inhibitors toward drug resistance of β-lactam antibiotics.Communicated by Ramaswamy H. Sarma.